The overall goal of the proposed research is to develop new radiolabeled peptide- and monoclonal antibody (mAb)-based agents for PET imaging and internal emitter therapy (IET) of breast and ovarian cancer. Breast and ovarian tumor targeting molecules will be conjugated to the marcrocyclic chelating agent TETA and labeled with the positron- and beta-emitting radionuclide 64Cu. The hypotheses to be addressed in this proposal are: 1) rapid and specific tumor targeting of 64Cu (T1/2=12.8 h) by compounds with short biological half-lives, such as peptide hormones and effector molecules for pretargeted mAbs, will significantly improve tumor/normal tissue contrast, tumor cell kill efficacy, and normal organ toxicity; and 2) in targeted radiotherapy, dose fractionation of 64Cu is more effective and less toxic than single high dose administration. The specific aims of the proposal are to 1) compare the tumor targeting capability and therapeutic efficacy of the mAb pretargeting system 64Cu- TETA-biotin/SA-NR-LU-10 with that of the covalently radiolabeled mAb 64Cu-BAT-2IT-NR-LU-10, 2) compare the toxicity of 64Cu-TETA-biotin/SA- NR-LU-10, and 64Cu-BAT-2IT-NR-LU-10, 3) synthesize 64Cu-labeled analogs of the peptide hormone luteinizing hormone-releasing hormone (LHRH) and evaluate them as potential PET and IET agents for breast and ovarian cancer, and 4) evaluate whether dose fractionation regimens of 64Cu- labeled LHRH analogs and pretargeted 64Cu-labeled biotin are more effective and less toxic than a single high dose. These goals will be accomplished by performing biodistribution (Aims 1 and 3), autoradiography (Aim 1), and therapy studies (Aims 1, 3, and 4) in tumor-bearing SCID mice, as well as by determining the maximum tolerated doses in normal mice and estimating human absorbed doses by performing PET imaging of a female baboon (Aim 2). If successful, the proposed studies will lead to the clinical evaluation of these 64 Cu-labeled agents for targeted radiotherapy of breast and ovarian cancer.